Giulia Tamborino1,2, Marijke De Saint-Hubert1, Lara Struelens1, Dayana C Seoane1, Eline A M Ruigrok2,3, An Aerts4, Wiggert A van Cappellen5, Marion de Jong2, Mark W Konijnenberg2, Julie Nonnekens6,7,8. 1. Research in Dosimetric Application, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium. 2. Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. 3. Department of Experimental Urology, Erasmus MC, Rotterdam, The Netherlands. 4. Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium. 5. Erasmus Optical Imaging Centre, Erasmus MC, Rotterdam, The Netherlands. 6. Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. j.nonnekens@erasmusmc.nl. 7. Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands. j.nonnekens@erasmusmc.nl. 8. Oncode Institute, Erasmus MC, Rotterdam, The Netherlands. j.nonnekens@erasmusmc.nl.
Abstract
BACKGROUND: Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. Therefore, we have built a refined cellular dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. METHODS: Time activity curves were measured and modeled for medium, membrane-bound, and internalized activity fractions over 6 days. Clonogenic survival assays were performed at various added activities (0.1-2.5 MBq/ml). 3D microscopy images (stained for cytoplasm, nucleus, and Golgi) were used as reference for developing polygonal meshes (PM) in 3DsMax to accurately render the cellular and organelle geometry. Absorbed doses to the nucleus per decay (S values) were calculated for 3 cellular morphologies: spheres (MIRDcell), truncated cone-shaped constructive solid geometry (CSG within MCNP6.1), and realistic PM models, using Geant4-10.03. The geometrical set-up of the clonogenic survival assays was modeled, including dynamic changes in proliferation, proximity variations, and cell death. The absorbed dose to the nucleus by the radioactive source cell (self-dose) and surrounding source cells (cross-dose) was calculated applying the MIRD formalism. Finally, the correlation between absorbed dose and survival fraction was fitted using a linear dose-response curve (high α/β or fast sub-lethal damage repair half-life) for different assumptions, related to cellular shape and localization of the internalized fraction of activity. RESULTS: The cross-dose, depending on cell proximity and colony formation, is a minor (15%) contributor to the total absorbed dose. Cellular volume (inverse exponential trend), shape modeling (up to 65%), and internalized source localization (up to + 149% comparing cytoplasm to Golgi) significantly influence the self-dose to nucleus. The absorbed dose delivered to the nucleus during a clonogenic survival assay is 3-fold higher with MIRDcell compared to the polygonal mesh structures. Our cellular dosimetry model indicates that 177Lu-DOTATATE treatment might be more effective than suggested by average spherical cell dosimetry, predicting a lower absorbed dose for the same cellular survival. Dose-rate effects and heterogeneous dose delivery might account for differences in dose-response compared to x-ray irradiation. CONCLUSION: Our results demonstrate that modeling of cellular and organelle geometry is crucial to perform accurate in vitro dosimetry.
BACKGROUND: Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. Therefore, we have built a refined cellular dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. METHODS: Time activity curves were measured and modeled for medium, membrane-bound, and internalized activity fractions over 6 days. Clonogenic survival assays were performed at various added activities (0.1-2.5 MBq/ml). 3D microscopy images (stained for cytoplasm, nucleus, and Golgi) were used as reference for developing polygonal meshes (PM) in 3DsMax to accurately render the cellular and organelle geometry. Absorbed doses to the nucleus per decay (S values) were calculated for 3 cellular morphologies: spheres (MIRDcell), truncated cone-shaped constructive solid geometry (CSG within MCNP6.1), and realistic PM models, using Geant4-10.03. The geometrical set-up of the clonogenic survival assays was modeled, including dynamic changes in proliferation, proximity variations, and cell death. The absorbed dose to the nucleus by the radioactive source cell (self-dose) and surrounding source cells (cross-dose) was calculated applying the MIRD formalism. Finally, the correlation between absorbed dose and survival fraction was fitted using a linear dose-response curve (high α/β or fast sub-lethal damage repair half-life) for different assumptions, related to cellular shape and localization of the internalized fraction of activity. RESULTS: The cross-dose, depending on cell proximity and colony formation, is a minor (15%) contributor to the total absorbed dose. Cellular volume (inverse exponential trend), shape modeling (up to 65%), and internalized source localization (up to + 149% comparing cytoplasm to Golgi) significantly influence the self-dose to nucleus. The absorbed dose delivered to the nucleus during a clonogenic survival assay is 3-fold higher with MIRDcell compared to the polygonal mesh structures. Our cellular dosimetry model indicates that 177Lu-DOTATATE treatment might be more effective than suggested by average spherical cell dosimetry, predicting a lower absorbed dose for the same cellular survival. Dose-rate effects and heterogeneous dose delivery might account for differences in dose-response compared to x-ray irradiation. CONCLUSION: Our results demonstrate that modeling of cellular and organelle geometry is crucial to perform accurate in vitro dosimetry.
Entities:
Keywords:
Cellular dosimetry; Polygonal mesh; S values; [177Lu]Lu-DOTA-[Tyr3]octreotate; in vitro cytotoxicity correlation
Authors: Giulia Tamborino; Yann Perrot; Marijke De Saint-Hubert; Lara Struelens; Julie Nonnekens; Marion De Jong; Mark W Konijnenberg; Carmen Villagrasa Journal: J Nucl Med Date: 2021-09-09 Impact factor: 11.082
Authors: Giulia Tamborino; Julie Nonnekens; Marijke De Saint-Hubert; Lara Struelens; Danny Feijtel; Marion de Jong; Mark W Konijnenberg Journal: J Nucl Med Date: 2021-04-09 Impact factor: 11.082
Authors: Eline A M Ruigrok; Giulia Tamborino; Erik de Blois; Stefan J Roobol; Nicole Verkaik; Marijke De Saint-Hubert; Mark W Konijnenberg; Wytske M van Weerden; Marion de Jong; Julie Nonnekens Journal: Eur J Nucl Med Mol Imaging Date: 2022-05-12 Impact factor: 10.057
Authors: An Aerts; Uta Eberlein; Sören Holm; Roland Hustinx; Mark Konijnenberg; Lidia Strigari; Fijs W B van Leeuwen; Gerhard Glatting; Michael Lassmann Journal: Eur J Nucl Med Mol Imaging Date: 2021-04-29 Impact factor: 9.236